The cause of juvenile diabetes mellitus (JDM) or insulin dependent diabetes mellitus, remains to be fully elucidated. Viral agents and pancreatic cell autoimmunity may have importance in the pathogenesis of the disease. Thus, JDM may begin with viral pancreatitis, and be propagated by the exposure of sequestered Beta-cell antigens and/or persistance of viral antigens in the Beta cells, with the subsequent development of autoaggressive phenomena. Insulin may also have a sensitizing effect against the Beta cell. We have recently been able to grow human insulinoma cells in culture. This cell line appears to be an excellent model Beta-cell target for immunological studies. Both circulating autoantibodies and sensitized lymphocytes to this model Beta cell have been demonstrated in JDM. The goal of the proposed studies is to delineate the cause and pathogenesis of JDM. The experiments are designed to demonstrate: 1. Cell mediated immunity of JDM against viral agents by: (a) Microassay of migration-inhibitory factors and lymphocyte mediated cytolysis against virus-infected target cells and (b) Parallel study of an animal model with virus-induced JDM-like disease. 2. Autoaggression against Beta cells by: (a) Estimation of the prevalence of circulating anti-Beta cell antibodies among JDM patients and members of their families. (b) Definition of the mechanisms of Beta cell destruction by subpopulations of human lymphocytes. (c) Investigation of delayed type hypersensitivity by sensitized lymphocytes against Beta cell organelles such as mitochondria. The results of these studies should provide the data needed to test the hypothesis that single or multiple viral infections of the pancreas initiate the autoimmune destruction of Beta-cells and thus the onset of overt diabetes.